Cyanoguanidines as cell proliferation inhibitors

ABSTRACT

Compounds of the following formula are used for inhibiting cell proliferation:                    
     wherein R, Q1, Q2, X are as defined in the specification.

This application is the national phase of international applicationPCT/DK98/00199 filed May 15, 1998 now WO98/54,146 which designated theU.S.

This invention relates to a hitherto unknown class of compounds whichshows strong activity in inhibiting undesirable cell proliferation ofe.g. skin cells and cancer cells, to pharmaceutical preparationscontaining these compounds, to dosage units of such preparations, and totheir use in the treatment and prophylaxis of diseases characterized byabnormal cell differentiation and/or cell proliferation such as e.g.psoriasis and cancer.

The compounds of the present invention are represented by the generalformula I

or their tautomeric forms, the attachment to the pyridine ring being inthe 3- or 4-position, in which formula R stands for one or moresubstituents which can be the same or different and are selected fromthe group consisting of: hydrogen, halogen, trifluoromethyl, C₁-C₄alkyl, alkoxy or alkyloxycarbonyl, nitro, amino or cyano and X standsfor direct bonding, substituted C₃-C₇ cydoalkylene, divalentheterocyclic ring (with one or more nitrogen, oxygen or sulfur),arylene, oxygen, one or two sulfur or amino which can be substituted byhydrogen or C₁-C₄ alkyl; and Q₁ and Q₂ stands for C₁-C₁₀ divalenthydrocarbon radical which can be straight, branched, cyclic, saturatedor unsaturated.

If the present compounds contain one or more asymmetric carbon atoms,these compounds may form optical isomers or diastereoisomers. Thepresent invention also comprises such isomers, and mixtures of same.

The present salts of the compounds of formula I may be formed withpharmaceutically acceptable inorganic or organic acids, such ashydrochloric, hydrobromic and hydroiodic acid, phosphoric acid, sulfuricacid, nitric acid, 4-toluenesulfonic acid, methanesulfonic acid, formicacid, acetic acid, propionic acid, citric acid, tartaric acid, succinicacid, benzoic acid and maleic acid and lithium, sodium, potassium,magnesium, calcium salts, as well as with ammonia, C1-C6-alikylamines,C1-C6 alkanolamines, procaine, cycloalkylamines, benzylamines andheterocyclic amines.

Even if the present compounds are well absorbed after enteraladministration, in some cases it can be advantageous to prepare suitablebioreversible derivatives of compounds of the invention, i.e. to prepareso-called prodrugs, preferably derivatives, the physicochemicalproperties of which leads to improved solubility at physiological pHand/or absorption and/or bioavailability of the compound in question.

Such derivatives are for instance pyridyl N-oxide derivatives ofcompounds of the invention, such compounds being prepared by oxidationof the pyridyl N by a suitable oxidizing agent, e.g. with3-chloro-perbenzoic acid in an inert solvent, e.g. dichloromethane.

Other suitable methods to improve the physicochemical properties and/orsolubility of the compounds concerned can be used as well.

N-Alkyl-N′-cyano-N″-pyridylguanidines, described in United KingdomPatent No. 1,489,879, are potent potassium channel activators with apronounced effect as pre-capillary vasodilators, reducing the totalperipheral resistance in animals and in man, and are thus useful asantihypertensives. As stated in the International Patent No.PCT/DK93/00291, filing date Sep. 13, 1993, Publication No. WO 94/06770the introduction of aryloxy-containing radicals into the aliphaticgroups from the above-cited U.K. Patent has led to structures showingmore specific pharmacological effects on isolated tissues and cells andwith no or a negligible effect on ⁸⁶Rb-efflux from potassium channels,as compared with the established effect of compounds covered by theabove-mentioned U.K. Patent.

The compounds of the present invention inhibit the proliferation ofvarious tumour cell lines in cultures at lower concentrations than theknown compounds, confer Table 1 below, thus making them potentiallyuseful in anfineoplastic chemotherapy.

The inhibition of tumour cell proliferation was studied using differenttypes of human cancer cell lines. The cell lines under investigationwere small cell lung carcinoma (NYH), non small cell lung carcinoma(NCI-H460), and breast cancer (MCF-7) using the following generalprocedure:

The cells were cultured in vitro for 24 hours in the presence of thecompound under investigation. DNA synthesis was measured byincorporation of [3H]thymidine, and the median inhibitory concentrations(IC₅₀) of the compounds were calculated.

TABLE 1 Inhibition of tumour cell proliferation in vitro in human breastcancer (MCF-7), human small cell lung carcinoma (NYH) and human nonsmall cell lung cancer (NCI-H460) cell lines by compounds of thefollowing examples of the present invention. MCF-7 NYH NCI-H460 Compoundfrom IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) Example No. 6 26 4.4 65 Example No. 86.6 0.91 65 Example No. 14 13 0.5 69 Prior art A 920 380 >1000 Prior artB 250 45 67 A: N-Cyano-N′-(4-phenoxybutyl)-N″-4-pyridylguanidine, inPCT/DK93/00291, example 14. B:N-Cyano-N′-(5-phenoxypentyl)-N″-4-pyridylguanidine, in PCT/DK93/00291,example 18.

The results show that the compounds of the present invention are able toinhibit the proliferation of tumour cells in vitro at the same or lowerconcentrations than the compounds A and B from PCT/DK93/00291.

The compounds of the invention are well tolerated and non-toxic and areexerting the described beneficial activities with no or minimal effecton the systemic blood pressure. In general, they may be administered byoral, intravenous, intraperitoneal, intranasal or transdermal routes.

The present invention also relates to methods for preparing the desiredcompounds of the general formula I. The compounds of the formula I mayconveniently be prepared by standard procedures detailed in the art. Theroutes are outlined in the following reaction scheme.

The present compounds are intended for use in pharmaceuticalcompositions which are useful in the treatment of the above mentioneddiseases.

The amount required of a compound of formula (I) (hereinafter referredto as the active ingredient) for therapeutic effect will, of course,vary both with the particular compound, the route of administration andthe mammal under treatment. A suitable dose of a compound of formula (I)for systemic treatment is 0.1 to 400 mg per kilogram bodyweight, themost preferred dosage being 1.0 to 100 mg per kg of mammal bodyweight,for example 5 to 20 mg/kg; administered once or more times daily.

A daily dose (for adults) may amount to 1 mg to 10000 mg, preferablyfrom 70-5000 mg, and in the veterinary practice correspondingly, indaily doses from 0.1 to 400 mg/kg bodyweight.

While it is possible for an active ingredient to be administered aloneas the raw chemical, it is preferable to present it as a pharmaceuticalformulation. Conveniently, the active ingredient comprises from 0.1% to99% by weight of the formulation. Conveniently, dosage units of aformulation contain between 0.5 mg and 1 g of the active ingredient. Fortopical administration, the active ingredient preferably comprises from1% to 20% by weight of the formulation but the active ingredient maycomprise as much as 50% w/w. Formulations suitable for nasal or buccaladministration may comprise 0.1% to 20% w/w. for example about 2% w/w ofactive ingredient.

By the term “dosage unit” is meant a unitary, i.e. a single dose whichis capable of being administered to a patient, and which may be readilyhandled and packed, remaining as a physically and chemically stable unitdose comprising either the active material as such or a mixture of itwith solid or liquid pharmaceutical diluents or carriers.

The formulations, both for veterinary and for human medical use, of thepresent invention comprise an active ingredient in association with apharmaceutically acceptable carrier therefor and optionally othertherapeutic ingredient(s). The carrier(s) must be “acceptable” in thesense of being compatible with the other ingredients of the formulationsand not deleterious to the recipient thereof.

The formulations include those in a form suitable for oral, rectal,parenteral (including subcutaneous, intramuscular, intravenous andintraperitoneal) administration.

The formulations may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing the active ingredient into association with a liquidcarrier or a finely divided solid carrier or both, and then, ifnecessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administrationmay be in the form of discrete units as capsules, sachets, tablets orlozenges, each containing a predetermined amount of the activeingredient; in the form of a powder or granules; in the form of asolution or a suspension in an aqueous liquid or non-aqueous liquid; orin the form of an oil-in-water emulsion or a water-in-oil emulsion. Theactive ingredient may also be administered in the form of a bolus,electuary or paste.

Formulations for rectal administration may be in the form of asuppository incorporating the active ingredient and a carrier such ascocoa butter, or in the form of an enema.

Formulations suitable for parenteral administration convenientlycomprise a sterile oily or aqueous preparation of the active ingredientwhich is preferably isotonic with the blood of the recipient.

In addition to the aforementioned ingredients, the formulations of thisinvention may include one or more additional ingredients, such asdiluents, buffers, flavouring agents, binders, surface active agents,thickeners, lubricants, preservatives, e.g. methylhydroxybenzoate(including anti-oxidants), emulsifying agents and the like.

The compositions may further contain other therapeutically activecompounds usually applied in the treatment of the above mentionedpathological conditions, e.g. antineoplastic agents which may result insynergistic effects on tumour cells.

The invention will now be further described in the following generalprocedures and examples:

The exemplified compounds I are listed in table 2.

TABLE 2 Com- pound Example 3- or 4- No. No. R Pyridyl Q₁ Q₂ X 101 1 H 41-CH₂ 4-CH₂ phenylene 102 2 H 4 (CH₂)₅ (CH₂)₄ — 103 3 H 3 (CH₂)₃ (CH₂)₄— 104 4 H 3 (CH₂)₂ (CH₂)₂ S-S 105 5 H 3 (CH₂)₃ (CH₂)₃ — 106 6 H 3 (CH₂)₆(CH₂)₆ — 107 7 H 3 (CH₂)₄ (CH₂)₄ — 108 8 H 4 (CH₂)₅ (CH₂)₅ — 109 9 H 4(CH₂)₄ (CH₂)₄ — 110 10  H 4 1-CH₂ 4-CH₂ cyclo- hexylene 111 11  H 4(CH₂)₃ (CH₂)₃ — 112 12  H 3 (CH₂)₂ CH₂ — 113 13  H 3 CH₂ CH₂ — 114 14  H4 (CH₂)₆ (CH₂)₆ — 115 15  H 3 (CH₂)₅ (CH₂)₅ — 116 16  2,6-Cl₂ 4 (CH₂)₅(CH₂)₅ — 117 17  6-OCH₃ 3 (CH₂)₅ (CH₂)₅ —

All melting points are uncorrected. For ¹H nuclear magnetic resonance(NMR) spectra (300 MHz) chemical shift values (δ) are quoted, unlessotherwise specified, for hexadeuterodimethylsulfoxide solutions relativeto internal tetramethylsilane (δ 0.00). The value for a multiplet (m),either defined (doublet (d), triplet (t), quartet (q)) or not at theapproximate mid point is given unless a range is quoted (s singlet, bbroad). The following abbreviations and formulas are used: DCCD(N,N′-dicyclohexylcarbodiimide), NH₂CN (cyanamide), Et₃N(triethylamine), DMF (dimethylformamide), DMAP (dimethylaminopyridine),MeOH (methanol), CH₂Cl₂ (methylenechloride) and DMSO-d₆(hexadeuterodimethylsulfoxide).

General Procedure 1: Coupling of Compounds of the General Formula IIwith Compounds of the General Formula III Resulting in Compounds of theGeneral Formula I.

A compound of the general formula II (6 mmol), a compound of the generalformula III (3 mmol) and triethylamine (6 mmol) in pyridine (4 ml) werestirred at room temperature. 4-Dimethylaminopyridine (DMAP, 10 mg) wasadded and the solution was stirred at 95° C. for 6 hours.

To the mixture was added ether (10 ml) and the resulting suspension wasfiltered and washed with ether to leave the crystalline product offormula I.

General Procedure 2: Conversion of Compounds of the General Formula IVinto Compounds of the General Formula I.

To a compound of the general formula IV (4 mmol) in dimethylformamide (3ml) was added dicyclohexylcarbodiimide (12 mmol), cyanamide (12 mmol)and triethylamine (0.4 ml). The reaction mixture was kept at roomtemperature for 4 days, when it was evaporated in vacuo (0.5 mmHg).

The residue was triturated with 3 portions of petroleum ether. Afterdecanting, the solid was stirred with acetone (15 ml), and thesuspension was filtered and washed with acetone to leave a mixture ofthe product of general formula I and N,N′-dicyclohexylthiourea.Extraction with dilute hydrochloric acid (1 N, 16 ml) andreprecipitation from the filtrate with dilute sodium hydroxide affordedthe crude product of the general formula I which was crystallized fromethanol.

General Procedure 3: Coupling of Compounds of the General Formula V withCompounds of the General Formula III Resulting in Compounds of theGeneral Formula I.

A mixture of a compound of the general formula V (15 mmol), a compoundof the general formula III (7.5 mmol) and diisopropylethylamine (15mmol) in dimethylformamide (10 ml) was stirred at room temperature. Tothe resulting solution was added dicyclohexylcarbodiimide (16.5 mmol).The formed suspension was stirred for 2 days at room temperature and wasthen evaporated in vacuo (0.5 mmHg). The residue was triturated with 3portions of petroleum ether (40 ml). After decanting, the solid wasstirred with water (100 ml) containing hydrochloric acid (4 N, 6 ml).After filtration, the pH of the aqueous filtrate was adjusted to 7.5with 2 N. sodium hydroxide. The precipitate was stirred at 0° C. andcollected by filtration and washings with water. Recrystallization fromaqueous acetone afforded the pure compound of the general formula I.

EXAMPLE 1 α,α′-Bis(N′-cyano-N″-4-pyridylguanidino)4-xylene (Compound101)

General procedure 1.

Starting compound II: S-Methyl N-cyano-N′-4-pyridylisothiourea.

Starting compound III: 4-Xylenediamine.

Purification: Acetone was added to the reaction mixture. Filtration andwashing with acetone resulted in the pure crystalline product.

¹H NMR (DMSO-d₆) δ: 9.38 (bs, 2H), 8.37 (d, 4H), 8.37 (bs, 2H), 7.32 (s,4H), 7.19 (d, 4H), 4.47 (bs, 4H).

EXAMPLE 2 1.9-Bis(N′-cyano-N″-4-pyridylguanidino)nonane (Compound 102)

General procedure 1.

Starting compound II: S-Methyl N-cyano-N′-4-pyridylisothiourea.

Starting compound III: 1,9-Diaminononane.

Purification: Recrystallization from aqueous acetone.

¹H NMR (DMSO-d₆) δ: 9.35 (bs, 2H), 8.38 (m, 4H), 7.82 (bs, 2H), 7.20(bd, 4H), 3.26 (bt, 4H), 1.52 (m, 4H), 1.28 (bs, 10H).

EXAMPLE 3 1,7-Bis(N′-cyano-N″-3-pyridylguanidino)heptane (Compound 103)

General procedure 1.

Starting compound II: S-Methyl N-cyano-N′-3-pyridylisothiourea.

Starting compound III: 1,7-Diaminoheptane.

Purification: The product was suspended in acetone, filtered and washedwith acetone.

¹H NMR (DMSO-d₆) δ: 9.06 (bs, 2H), 8.45 (d, 2H), 8.33 (dd, 2H), 7.66 (m,2H), 7.43 (bt, 2H), 7.37 (dd, 2H), 3.21 (q, 4H), 1.51 (m, 4H), 1.29 (bs,6H).

EXAMPLE 4 2,2′-Bis(N′-cyano-N″-3-pyridylguanidino)diethyl disulfide(Compound 104)

General procedure 1.4 Equivalents of triethylamine were used.

Starting compound II: S-Methyl N-cyano-N′-3pyridylisothiourea.

Starting compound III: Bis (2-aminoethyl)disulfide, dihydrochloride.

Purification: Recrystallization from aqueous acetone.

¹H NMR (DMSO-d₆) δ: 9.25 (bs, 2H), 8.48 (d, 2H), 8.36 (dd, 2H), 7.67 (m,2H) 7.54 (bt, 2H), 7.39 (dd, 2H), 3.52 (q, 4H), 2.92 (t, 4H).

EXAMPLE 5 1,6-Bis(N′-cyano-N″-3-pyridylguanidino)hexane (Compound 105)

General procedure 1.

Starting compound II: S-Methyl N-cyano-N′-3-pyridylisothiourea.

Starting compound III: 1,6-Diaminohexane.

Purification: The crystalline product was suspended in acetone, filteredand washed with acetone.

¹H NMR (DMSO-dr) δ: 8.98 (bs, 2H), 8.46 (d, 2H), 8.33 (dd, 2H), 7.66 (m,2H), 7.44 (bs, 2H), 7.37 (dd, 2H), 3.22 (m, 4H), 1.52 (m, 4H), 1.30 (m,4H).

EXAMPLE 6 1,12-Bis(N′-cyano-N″-3-pyridylguanidino)dodecane (Compound106)

General procedure 1.

Starting compound II: S-Methyl N-cyano-N′-3-pyridylisothiourea.

Starting compound III: 1,12-Diaminododecane.

Purification: Recrystallization from aqueous acetone.

¹H NMR (DMSO-d₆) δ: 9.06 (bs, 2H), 8.45 (d, 2H), 8.33 (m, 2H), 7.66 (m,2H), 7.43 (bs, 2H), 7.37 (dd, 2H), 3.21 (bs, 4H), 1.50 (m, 4H), 1.26(bs, 16H).

EXAMPLE 7 1,8-Bis(N′-cyano-N″-3-pyridylguanidino)octane (Compound 107)

General procedure 1.

Starting compound II: S-Methyl N-cyano-N′-3pyridylisothiourea.

Starting compound III: 1,8-Diaminooctane.

Purification: Recrystallization from aqueous acetone.

¹H NMR (DMSO-d₆) δ: 9.06 (bs, 2H), 8.45 (d, 2H), 8.33 (dd, 2H), 7.66 (m,2H), 7.41 (bt, 2H), 7.36 (dd, 2H), 3.21 (q, 4H), 1.51 (m, 4H), 1.29 (bs,8H).

EXAMPLE 8 1,10-Bis(N′-cyano-N″-4-pyridylguanidino)decane (Compound 108)

General procedure 1.

Starting compound II: S-Methyl N-cyano-N′-4-pyridylisothiourea.

Starting compound III: 1,10-Diaminodecane.

Purification: Recrystallization from aqueous acetone.

¹H NMR (DMSO-d₆) δ: ˜10 (bs, 2H), 8.42 (d, 4H), 8.02 (bt, 2H), 7.29 (bd,4H), 3.29 (q, 4H), 1.52 (m, 4H), 1.27 (bs, 12H).

EXAMPLE 9 1,8-Bis(N′-cyano-N″-4-pyridylguanidino)octane (Compound 109)

General procedure 1.

Starting compound II: S-Methyl N-cyano-N′-4-pyridylisothiourea.

Starting compound III: 1,8-Diaminooctane.

Purification: Recrystallization from aqueous methanol.

¹H NMR (DMSO-d₆) δ: 9.34 (bs, 2H), 8.38 (m, 4H), 7.82 (bs, 2H), 7.20(bd, 4H), 3.26 (t, 4H), 1.52 (m, 4H), 1.29 (bs, 8H).

EXAMPLE 10 1,4-Bis(N′-cyano-N″-4-pyrdylguanidinomethyl)cyclohexane(Compound 110)

General procedure 1.

Starting compound II: S-Methyl N-cyano-N′-4-pyridylisothiourea.

Starting compound III: 1,4-Bis(aminomethyl)cyclohexane.

Purification: The crystalline product was suspended in methanol,filtered and washed with methanol.

¹H NMR (DMSO-d₆) δ: 9.00 (bs, 2H), 8.38 (m, 4H), 7.81 (bs, 2H), 7.19 (m,4H), 3.15 (d, 4H), 1.76 (m, 4H), 1.60-1.30 (m, 2H), 0.93 (m, 4H).

EXAMPLE 11 1,6-Bis(N′-cyano-N″-4-pyridylguanidino)hexane (Compound 111)

General procedure 2.

Starting compound IV: 1,6-Bis(N′-4-pyridylthioureido)hexane

Purification: Flash chromatography (Silica gel, eluent 0-22% MeOH inCH₂Cl₂) followed by crystallization from ether/acetone.

¹H NMR (DMSO-d₆) δ: 9.39 (bs, 2H), 8.38 (bd, 4H), 7.84 (bs, 2H), 7.21(m, 4H), 3.27 (m, 4H), 1.53 (m, 4H), 1.32 (m, 4H).

EXAMPLE 12 1,3-Bis(N′-cyano-N″-3-pyridylguanidino)propane (Compound 112)

General procedure 3.

Starting compound V: N-Cyano-N′-3-pyridylthiourea.

Starting compound III: 1,3-Diaminopropane.

Purification: General procedure.

M.p. 148-148.5° C.

¹H NMR (DMSO-d₆) δ: 9.14 (bs, 2H), 8.55 (d, 2H), 8.42 (dd, 2H), 7.80 (m,2H), 7.60-7.30 (m, 4H), 3.46 (t, 4H), 1.78 (m, 2H).

EXAMPLE 13 1,2-Bis(N′-cyano-N″-3-pyridylguanidino)ethane (Compound 113)

General procedure 3.

Starting compound V: N-Cyano-N′-3-pyridylthiourea.

Starting compound III: 1,2-Diaminoethane.

Purification: General procedure.

M.p. 146.5-147.5° C.

¹H NMR (DMSO-d₆) δ: 9.16 (bs, 2H), 8.48 (d, 2H), 8.38 (dd, 2H), 7.69(bd, 2H), 7.43 (bs, 2H), 7.41 (dd, 2H), 3.38 (bs, 4H).

EXAMPLE 14 1,12-Bis(N′-cyano-N″-4-pyridylguanidino)dodecane (Compound114)

General procedure 1

Starting compound II: S-Methyl N-cyano-N′-4-pyridylisothiourea.

Starting compound III: 1,12-Diaminododecane.

Purification: Flash chromatography (Silica gel, eluent 0-20% MeOH inCH₂Cl₂) followed by crystallisation from methanol/ether.

¹H NMR (DMSO-d₆) δ: 9.35 (bs, 2H), 8.38 (m, 4H), 7.83 (bt, 2H), 7.21(bs, 4H), 3.26 (q, 4H), 1.51 (m, 4H), 1.25 (bs, 16H).

EXAMPLE 15 1,10-Bis(N′-cyano-N″-3-pyridylguanidino)decane (Compound 115)

General procedure 1

Starting compound II: S-Methyl N-cyano-N′-3pyridylisothiourea.

Starting compound III: 1,10-Diaminodecane.

Purification: Recrystallization from aqueous acetone.

¹H NMR (DMSO-d₆) δ: 9.06 (bs, 2H), 8.45 (d, 2H), 8.33 (dd, 2H), 7.66 (m,2H), (bt, 2H), 7.37 (m, 2H), 3.21 (q, 4H), 1.50 (m, 4H), 1.27 (m, 12H).

EXAMPLE 16 1,10-Bis(N′-cyano-N″-(2,6-dichloro-4-pyridyl)guanidino)decane(Compound 116)

General procedure 1

Starting compound II: S-MethylN-cyano-N′-(2,6-dichloro-4-pyridyl)isothiourea.

Starting compound III: 1,10-Diaminodecane.

Purification: Recrystallization from aqueous acetone and fromacetone/ether.

1H NMR (DMSO-d6) δ: 9.82 (bs, 2H), 8.13 (bs, 2H), 7.31 (bs, 4H), 3.27(m, 4H), 1.51 (m, 4H), 1.27 (m, 12H).

EXAMPLE 17 1,10-Bis(N′-cyano-N″-(2-methoxy-5-pyridyl)guanidino)decane(Compound 117)

General procedure 1

Starting compound II: S-Methyl N-cyano-N′-(2-methoxy-5-pyridyl)isothiourea.

Starting compound III: 1,10-Diaminodecane.

Purification: Flash chromatography (Eluent 1% NH₃(aq) and 0-30% MeOH inCH₂Cl₂).

1 H NMR (DMSO-d6) δ: 8.80 (bs, 2H), 8.00 (d, 2H), 7.55 (dd, 2H), 7.06(bt, 2H), 6.82 (d, 2H), 3.84 (s, 6H), 3.14 (q, 4H), 1.46 (m, 4H), (m,12H).

EXAMPLE 18

Capsules 1 Capsule contains: 1,10-Bis(N′-cyano-N″-4-pyridylguanidino)-100 mg decane (active compound) Polyethylene Glycol 962 mg GelatineCapsule no. 00 Gelatine 122 mg

EXAMPLE 19

Tablets Manufacture of 10,000 tablets I1,10-Bis(N′-cyano-N″-4-pyridylguanidino)- 10,000 kg  decane (activecompound) Cross carmellose sodium 0,300 kg II Hydroxypropylmethylcellulose, 0,200 kg low viscosity type Sorbimacrogol oleate 0,010 kgPurified water q.s. III Crosscarmellose sodium 0,200 kg Coloidalanhydrous silica 0,050 kg Magnesium stearate 0,050 kg

I is mixed intimately in a highshear mixer, is wetted with II andgranulated into a moist mass. The moist granulate is dried in afluid-bed dryer at an inlet air temperature of 60° C. until the driedgranulate has a water activity of 0.3-0.4 (=in equilibrium with air of30-40% R.H.).

The dried granulate is passed through a sieve with mesh openings of 850micro meters.

The sieved granulate is finally mixed with III in a cone mixer.

The finished granulate is compressed into tablets of mass 1071 mg andsufficient hardness.

What we claim is:
 1. A compound of the formula I

or their tautomeric forms, the attachment to the pyridine ring being inthe 3- or 4-position, in which formula R stands for one or moresubstituents which can be the same or different and are selected fromthe group consisting of: hydrogen, halogen, trifluoromethyl, C₁-C₄alkyl, alkoxy or alkyloxycarbonyl, nitro, amino or cyano and X standsfor direct bonding, substituted C₃-C₇ cycloalkylene, arylene, oxygen,one or two sulfur or amino which can be substituted by hydrogen or C₁-C₄alkyl; and Q₁ and Q₂ stands for C₁-C₁₀ divalent hydrocarbon radicalwhich can be straight, branched, cyclic, saturated or unsaturated; andpharmaceutically acceptable, non-toxic salts and N-oxides thereof.
 2. Acompound according to formula I of claim 1, in which the attachment tothe pyridine ring is in the 4-position, in which formula R stands forhydrogen and X stands for direct bonding, substituted C₃-C₇cycloalkylene, arylene or one or two sulfur, and Q₁ and Q₂ stands forC₁-C₁₀ divalent hydrocarbon radical which can be straight, branched,saturated or unsaturated; and pharmaceutically acceptable, non-toxicsalts and N-oxides thereof.
 3. A salt according to claim 1 in which thesalt is selected from the group consisting of salts formed withhydrochloric, hydrobromic and hydroiodic acid, phosphoric acid,sulphuric acid, nitric acid, p-toluenesulphonic acid, methanesulphonicacid, formic acid, acetic acid, propionic acid, citric acid, tartaricacid, and maleic acid, and lithium, sodium, potassium, magnesium,calcium salts, as well as salts with ammonia, C₁-C₆-alkylamines, C₁-C₆alkanolamines, procaine, cycloalkylamines and benzylamines.
 4. Acompound of claim 1 which is selected from the group consisting of:1,12-bis(N′-cyano-N″-3-pyridylguanidinododecane;1,10-bis(N′-cyano-N″-4-pyridylguanidino)decane;1,12-bis(N′-cyano-N″-4-pyridylguanidino)dodecane; and their salts andpure enantiomeric forms.
 5. A pharmaceutical composition containing acompound to claim 1 and a pharmaceutically acceptable carrier.
 6. Amethod of inhibiting the proliferation of cancer cells selected fromlung carcinoma and breast cancer cells in a host which comprisesadministering to said host an effective amount of one or more compoundsaccording to claim
 1. 7. Method for producing a compound of formula Iaccording to claim 1, in which a) a compound of the general formula II

 in which R is as defined above, is reacted with a compound of thegeneral formula III

 in which Q₁, Q₂ and X are as defined above, in the presence oftriethylamine or another tertiary amine and 4-dimethylaminopyridine inpyridine or an inert solvent at room temperature or above; or b) acompound of the general formula II

 in which Q₁, Q₂, X and R are as defined above, is reacted withdicyclohexylcarbodiimide and cyanamide in the presence of triethytamineor another tertiary amine in acetonitrile or another inert solvent atroom temperature or above; or c) a compound of the general formula V

 in which R is as defined above, is reacted with a compound of thegeneral formula III

 in which Q₁, Q₂ and X are as defined above, in the presence ofdiisopropylethylamine or another tertiary amine in dimethytformamide oran inert solvent at roomtemperature or above.